Effects of Docosahexaenoic Acid and Its Peroxidation Product on Amyloid-β Peptide-Stimulated Microglia

  • Xue Geng
  • Bo Yang
  • Runting Li
  • Tao Teng
  • Mary Jo Ladu
  • Grace Y. Sun
  • C. Michael Greenlief
  • James C. LeeEmail author
Original Article


Growing evidence suggests that docosahexaenoic acid (DHA) exerts neuroprotective effects, although the mechanism(s) underlying these beneficial effects are not fully understood. Here we demonstrate that DHA, but not arachidonic acid (ARA), suppressed oligomeric amyloid-β peptide (oAβ)–induced reactive oxygen species (ROS) production in primary mouse microglia and immortalized mouse microglia (BV2). Similarly, DHA but not ARA suppressed oAβ-induced increases in phosphorylated cytosolic phospholipase A2 (p-cPLA2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α) in BV2 cells. LC-MS/MS assay indicated the ability for DHA to cause an increase in 4-hydroxyhexenal (4-HHE) and suppress oAβ-induced increase in 4-hydroxynonenal (4-HNE). Although oAβ did not alter the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway, exogenous DHA, ARA as well as low concentrations of 4-HHE and 4-HNE upregulated this pathway and increased production of heme oxygenase-1 (HO-1) in microglial cells. These results suggest that DHA modulates ARA metabolism in oAβ-stimulated microglia through suppressing oxidative and inflammatory pathways and upregulating the antioxidative stress pathway involving Nrf2/HO-1. Understanding the mechanism(s) underlying the beneficial effects of DHA on microglia should shed light into nutraceutical therapy for the prevention and treatment of Alzheimer’s disease (AD).


Alzheimer’s disease Fish oil Omega-3 fatty acids Phospholipase A2 Lipid peroxidation 



We thank Dr. Brian Mooney, associate director of the Charles W. Gehrke Proteomics Center at the University of Missouri, for providing assistance with the LC-MS/MS.

Funding Information

This study is supported by a National Institutes of Health grant R01-AG044404 (to J. C. L.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.


  1. 1.
    Sun GY, Simonyi A, Fritsche KL, Chuang DY, Hannink M, Gu Z, Greenlief CM, Yao JK et al (2018) Docosahexaenoic acid (DHA): an essential nutrient and a nutraceutical for brain health and diseases. Prostaglandins Leukot Essent Fat Acids 136:3–13. CrossRefGoogle Scholar
  2. 2.
    Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alperovitch A (2007) Dietary patterns and risk of dementia: the Three-City cohort study. Neurology 69(20):1921–1930. CrossRefPubMedGoogle Scholar
  3. 3.
    Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM (1997) Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 42(5):776–782. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Laitinen MH, Ngandu T, Rovio S, Helkala EL, Uusitalo U, Viitanen M, Nissinen A, Tuomilehto J et al (2006) Fat intake at midlife and risk of dementia and Alzheimer’s disease: a population-based study. Dement Geriatr Cogn Disord 22(1):99–107. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko-Mauro KA, Ellis L, LaFerla FM (2007) Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels. J Neurosci Off J Soc Neurosci 27(16):4385–4395. CrossRefGoogle Scholar
  6. 6.
    Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA et al (2005) A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci Off J Soc Neurosci 25(12):3032–3040. CrossRefGoogle Scholar
  7. 7.
    Hur J, Mateo V, Amalric N, Babiak M, Bereziat G, Kanony-Truc C, Clerc T, Blaise R et al (2018) Cerebrovascular beta-amyloid deposition and associated microhemorrhages in a Tg2576 Alzheimer mouse model are reduced with a DHA-enriched diet. FASEB J: official publication of the Federation of American Societies for Experimental Biology 32(9):4972–4983. fj201800200R. CrossRefGoogle Scholar
  8. 8.
    Pan Y, Choy KHC, Marriott PJ, Chai SY, Scanlon MJ, Porter CJH, Short JL, Nicolazzo JA (2018) Reduced blood-brain barrier expression of fatty acid-binding protein 5 is associated with increased vulnerability of APP/PS1 mice to cognitive deficits from low omega-3 fatty acid diets. J Neurochem 144(1):81–92. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Pan Y, Scanlon MJ, Owada Y, Yamamoto Y, Porter CJ, Nicolazzo JA (2015) Fatty acid-binding protein 5 facilitates the blood-brain barrier transport of docosahexaenoic acid. Mol Pharm 12(12):4375–4385. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Grimm MO, Haupenthal VJ, Mett J, Stahlmann CP, Blumel T, Mylonas NT, Endres K, Grimm HS et al (2016) Oxidized docosahexaenoic acid species and lipid peroxidation products increase amyloidogenic amyloid precursor protein processing. Neurodegener Dis 16(1–2):44–54. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yang X, Sheng W, Sun GY, Lee JCM (2011) Effects of fatty acid unsaturation numbers on membrane fluidity and α-secretase-dependent amyloid precursor protein processing. Neurochem Int 58(3):321–329. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yang X, Sun GY, Eckert GP, Lee JC (2014) Cellular membrane fluidity in amyloid precursor protein processing. Mol Neurobiol 50(1):119–129. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hjorth E, Zhu M, Toro VC, Vedin I, Palmblad J, Cederholm T, Freund-Levi Y, Faxen-Irving G et al (2013) Omega-3 fatty acids enhance phagocytosis of Alzheimer’s disease-related amyloid-beta42 by human microglia and decrease inflammatory markers. J Alzheimer’s Disease: JAD 35(4):697–713. CrossRefGoogle Scholar
  14. 14.
    Strokin M, Sergeeva M, Reiser G (2007) Prostaglandin synthesis in rat brain astrocytes is under the control of the n-3 docosahexaenoic acid, released by group VIB calcium-independent phospholipase A2. J Neurochem 102(6):1771–1782. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ong WY, Yeo JF, Ling SF, Farooqui AA (2005) Distribution of calcium-independent phospholipase A2 (iPLA2) in monkey brain. J Neurocytol 34(6):447–458. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Green JT, Orr SK, Bazinet RP (2008) The emerging role of group VI calcium-independent phospholipase A2 in releasing docosahexaenoic acid from brain phospholipids. J Lipid Res 49(5):939–944. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ramanadham S, Ali T, Ashley JW, Bone RN, Hancock WD, Lei X (2015) Calcium-independent phospholipases A2 and their roles in biological processes and diseases. J Lipid Res 56(9):1643–1668. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Sun GY, Chuang DY, Zong Y, Jiang J, Lee JC, Gu Z, Simonyi A (2014) Role of cytosolic phospholipase A2 in oxidative and inflammatory signaling pathways in different cell types in the central nervous system. Mol Neurobiol 50(1):6–14. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Calder PC (2008) The relationship between the fatty acid composition of immune cells and their function. Prostaglandins Leukot Essent Fat Acids 79(3–5):101–108. CrossRefGoogle Scholar
  20. 20.
    Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG (2004) Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci U S A 101(22):8491–8496. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Serhan CN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510(7503):92–101. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yang B, Fritsche KL, Beversdorf DQ, Gu Z, Lee JC, Folk WR, Greenlief CM, Sun GY (2019) Yin-yang mechanisms regulating lipid peroxidation of docosahexaenoic acid and arachidonic acid in the central nervous system. Front Neurol 10:642. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Stephenson DT, Lemere CA, Selkoe DJ, Clemens JA (1996) Cytosolic phospholipase A2 (cPLA2) immunoreactivity is elevated in Alzheimer’s disease brain. Neurobiol Dis 3(1):51–63. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lovell MA, Ehmann WD, Mattson MP, Markesbery WR (1997) Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer’s disease. Neurobiol Aging 18(5):457–461CrossRefGoogle Scholar
  25. 25.
    Markesbery WR, Lovell MA (1998) Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol Aging 19(1):33–36CrossRefGoogle Scholar
  26. 26.
    McGrath LT, McGleenon BM, Brennan S, McColl D, Mc IS, Passmore AP (2001) Increased oxidative stress in Alzheimer’s disease as assessed with 4-hydroxynonenal but not malondialdehyde. QJM 94(9):485–490CrossRefGoogle Scholar
  27. 27.
    Montine KS, Olson SJ, Amarnath V, Whetsell WO Jr, Graham DG, Montine TJ (1997) Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer’s disease is associated with inheritance of APOE4. Am J Pathol 150(2):437–443PubMedPubMedCentralGoogle Scholar
  28. 28.
    Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem 68(5):2092–2097CrossRefGoogle Scholar
  29. 29.
    Ayala A, Munoz MF, Arguelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Med Cell Longev 2014:360438. CrossRefGoogle Scholar
  30. 30.
    Long EK, Picklo MJ Sr (2010) Trans-4-hydroxy-2-hexenal, a product of n-3 fatty acid peroxidation: make some room HNE. Free Radic Biol Med 49(1):1–8. CrossRefGoogle Scholar
  31. 31.
    Cherkas A, Zarkovic N (2018) 4-Hydroxynonenal in redox homeostasis of gastrointestinal mucosa: implications for the stomach in health and diseases. Antioxidants (Basel) 7(9):E118. CrossRefGoogle Scholar
  32. 32.
    Siegel SJ, Bieschke J, Powers ET, Kelly JW (2007) The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation. Biochemistry 46(6):1503–1510. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Zheng R, Heck DE, Mishin V, Black AT, Shakarjian MP, Kong AN, Laskin DL, Laskin JD (2014) Modulation of keratinocyte expression of antioxidants by 4-hydroxynonenal, a lipid peroxidation end product. Toxicol Appl Pharmacol 275(2):113–121. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Nakagawa F, Morino K, Ugi S, Ishikado A, Kondo K, Sato D, Konno S, Nemoto K et al (2014) 4-Hydroxy hexenal derived from dietary n-3 polyunsaturated fatty acids induces anti-oxidative enzyme heme oxygenase-1 in multiple organs. Biochem Biophys Res Commun 443(3):991–996. CrossRefGoogle Scholar
  35. 35.
    Lin MH, Yen JH, Weng CY, Wang L, Ha CL, Wu MJ (2014) Lipid peroxidation end product 4-hydroxy-trans-2-nonenal triggers unfolded protein response and heme oxygenase-1 expression in PC12 cells: roles of ROS and MAPK pathways. Toxicology 315:24–37. CrossRefGoogle Scholar
  36. 36.
    Ishikado A, Nishio Y, Morino K, Ugi S, Kondo H, Makino T, Kashiwagi A, Maegawa H (2010) Low concentration of 4-hydroxy hexenal increases heme oxygenase-1 expression through activation of Nrf2 and antioxidative activity in vascular endothelial cells. Biochem Biophys Res Commun 402(1):99–104. CrossRefGoogle Scholar
  37. 37.
    Siow RC, Ishii T, Mann GE (2007) Modulation of antioxidant gene expression by 4-hydroxynonenal: atheroprotective role of the Nrf2/ARE transcription pathway. Redox Rep: Communications in Free Radical Research 12(1):11–15. CrossRefGoogle Scholar
  38. 38.
    Zhang M, Wang S, Mao L, Leak RK, Shi Y, Zhang W, Hu X, Sun B et al (2014) Omega-3 fatty acids protect the brain against ischemic injury by activating Nrf2 and upregulating heme oxygenase 1. J Neurosci Off J Soc Neurosci 34(5):1903–1915. CrossRefGoogle Scholar
  39. 39.
    Ishikado A, Morino K, Nishio Y, Nakagawa F, Mukose A, Sono Y, Yoshioka N, Kondo K et al (2013) 4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation. PLoS One 8(7):e69415. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Cohen G, Riahi Y, Sunda V, Deplano S, Chatgilialoglu C, Ferreri C, Kaiser N, Sasson S (2013) Signaling properties of 4-hydroxyalkenals formed by lipid peroxidation in diabetes. Free Radic Biol Med 65:978–987. CrossRefGoogle Scholar
  41. 41.
    Yang B, Li R, Michael Greenlief C, Fritsche KL, Gu Z, Cui J, Lee JC, Beversdorf DQ et al (2018) Unveiling anti-oxidative and anti-inflammatory effects of docosahexaenoic acid and its lipid peroxidation product on lipopolysaccharide-stimulated BV-2 microglial cells. J Neuroinflammation 15(1):202. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20(3):269–287CrossRefGoogle Scholar
  43. 43.
    Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JCM, Sajti E, Jaeger BN, O’Connor C et al (2017) An environment-dependent transcriptional network specifies human microglia identity. Science (New York, NY) 356(6344):eaal3222. CrossRefGoogle Scholar
  44. 44.
    Zuroff L, Daley D, Black KL, Koronyo-Hamaoui M (2017) Clearance of cerebral Abeta in Alzheimer’s disease: reassessing the role of microglia and monocytes. Cell Mol Life Sci. CrossRefGoogle Scholar
  45. 45.
    Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK, Puckett L, Farfara D, Kingery ND et al (2013) Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Commun 4:2030. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368(2):117–127. CrossRefGoogle Scholar
  47. 47.
    Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML et al (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43(5):429–435. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2):107–116. CrossRefGoogle Scholar
  49. 49.
    Koenigsknecht J, Landreth G (2004) Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J Neurosci Off J Soc Neurosci 24(44):9838–9846. CrossRefGoogle Scholar
  50. 50.
    Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43(5):436–441. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci Off J Soc Neurosci 29(38):11982–11992. CrossRefGoogle Scholar
  52. 52.
    Udan ML, Ajit D, Crouse NR, Nichols MR (2008) Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line. J Neurochem 104(2):524–533. CrossRefGoogle Scholar
  53. 53.
    Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, Loboda AA, Zhou Y et al (2017) TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170(4):649–663.e613. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wilkinson K, El Khoury J (2012) Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer’s disease. Int J Alzheimers Dis 2012:489456. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Yang CN, Shiao YJ, Shie FS, Guo BS, Chen PH, Cho CY, Chen YJ, Huang FL et al (2011) Mechanism mediating oligomeric Abeta clearance by naive primary microglia. Neurobiol Dis 42(3):221–230. CrossRefGoogle Scholar
  56. 56.
    Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M (2016) TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91(2):328–340. CrossRefGoogle Scholar
  57. 57.
    Yu Y, Ye RD (2015) Microglial Abeta receptors in Alzheimer’s disease. Cell Mol Neurobiol 35(1):71–83. CrossRefGoogle Scholar
  58. 58.
    Teng T, Dong L, Ridgley DM, Ghura S, Tobin MK, Sun GY, LaDu MJ, Lee JC (2018) Cytosolic phospholipase A2 facilitates oligomeric amyloid-β peptide association with microglia via regulation of membrane-cytoskeleton connectivity. Mol Neurobiol 56:3222–3234. CrossRefGoogle Scholar
  59. 59.
    Wilkinson BL, Landreth GE (2006) The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer’s disease. J Neuroinflammation 3:30. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374(6523):647–650. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Chuang DY, Simonyi A, Kotzbauer PT, Gu Z, Sun GY (2015) Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway. J Neuroinflammation 12:199. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yang B, Li R, Woo T, Browning JD Jr, Song H, Gu Z, Cui J, Lee JC et al (2019) Maternal dietary docosahexaenoic acid alters lipid peroxidation products and (n-3)/(n-6) fatty acid balance in offspring mice. Metabolites 9(3):40. CrossRefGoogle Scholar
  63. 63.
    Sun GY, Li R, Yang B, Fritsche KL, Beversdorf DQ, Lubahn DB, Geng X, Lee JC et al (2019) Quercetin potentiates docosahexaenoic acid to suppress lipopolysaccharide-induced oxidative/inflammatory responses, alter lipid peroxidation products, and enhance the adaptive stress pathways in BV-2 microglial cells. Int J Mol Sci 20(4):E932. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Szaingurten-Solodkin I, Hadad N, Levy R (2009) Regulatory role of cytosolic phospholipase A2alpha in NADPH oxidase activity and in inducible nitric oxide synthase induction by aggregated Abeta1-42 in microglia. Glia 57(16):1727–1740. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Amen DG, Harris WS, Kidd PM, Meysami S, Raji CA (2017) Quantitative erythrocyte omega-3 EPA plus DHA levels are related to higher regional cerebral blood flow on brain SPECT. J Alzheimer’s Disease: JAD 58(4):1189–1199. CrossRefGoogle Scholar
  66. 66.
    El Shatshat A, Pham AT, Rao PPN (2019) Interactions of polyunsaturated fatty acids with amyloid peptides Abeta40 and Abeta42. Arch Biochem Biophys 663:34–43. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Heras-Sandoval D, Pedraza-Chaverri J, Perez-Rojas JM (2016) Role of docosahexaenoic acid in the modulation of glial cells in Alzheimer’s disease. J Neuroinflammation 13(1):61. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Huang TL (2010) Omega-3 fatty acids, cognitive decline, and Alzheimer’s disease: a critical review and evaluation of the literature. J Alzheimer’s Disease: JAD 21(3):673–690. CrossRefGoogle Scholar
  69. 69.
    Pan Y, Khalil H, Nicolazzo JA (2015) The impact of docosahexaenoic acid on Alzheimer’s disease: is there a role of the blood-brain barrier? Curr Clin Pharmacol 10(3):222–241CrossRefGoogle Scholar
  70. 70.
    Rey C, Nadjar A, Joffre F, Amadieu C, Aubert A, Vaysse C, Pallet V, Layé S et al (2018) Maternal n-3 polyunsaturated fatty acid dietary supply modulates microglia lipid content in the offspring. Prostaglandins Leukot Essent Fat Acids 133:1–7. CrossRefGoogle Scholar
  71. 71.
    Hopperton KE, Trepanier MO, Giuliano V, Bazinet RP (2016) Brain omega-3 polyunsaturated fatty acids modulate microglia cell number and morphology in response to intracerebroventricular amyloid-beta 1-40 in mice. J Neuroinflammation 13(1):257. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Abdullah L, Evans JE, Emmerich T, Crynen G, Shackleton B, Keegan AP, Luis C, Tai L et al (2017) APOE epsilon4 specific imbalance of arachidonic acid and docosahexaenoic acid in serum phospholipids identifies individuals with preclinical mild cognitive impairment/Alzheimer’s disease. Aging 9(3):964–985. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Niazi ZR, Silva GC, Ribeiro TP, Leon-Gonzalez AJ, Kassem M, Mirajkar A, Alvi A, Abbas M et al (2017) EPA:DHA 6:1 prevents angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase- and COX-derived oxidative stress. Hyper Res: official journal of the Japanese Society of Hypertension 40(12):966–975. CrossRefGoogle Scholar
  74. 74.
    Lucena CF, Roma LP, Graciano MF, Veras K, Simoes D, Curi R, Carpinelli AR (2015) Omega-3 supplementation improves pancreatic islet redox status: in vivo and in vitro studies. Pancreas 44(2):287–295. CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Wales KM, Kavazos K, Nataatmadja M, Brooks PR, Williams C, Russell FD (2014) N-3 PUFAs protect against aortic inflammation and oxidative stress in angiotensin II-infused apolipoprotein E-/- mice. PLoS One 9(11):e112816. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Yamagata K, Tusruta C, Ohtuski A, Tagami M (2014) Docosahexaenoic acid decreases TNF-alpha-induced lectin-like oxidized low-density lipoprotein receptor-1 expression in THP-1 cells. Prostaglandins Leukot Essent Fat Acids 90(4):125–132. CrossRefGoogle Scholar
  77. 77.
    Depner CM, Philbrick KA, Jump DB (2013) Docosahexaenoic acid attenuates hepatic inflammation, oxidative stress, and fibrosis without decreasing hepatosteatosis in a Ldlr(-/-) mouse model of Western diet-induced nonalcoholic steatohepatitis. J Nutr 143(3):315–323. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Rahman M, Kundu JK, Shin JW, Na HK, Surh YJ (2011) Docosahexaenoic acid inhibits UVB-induced activation of NF-kappaB and expression of COX-2 and NOX-4 in HR-1 hairless mouse skin by blocking MSK1 signaling. PLoS One 6(11):e28065. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Levy R, Lowenthal A, Dana R (2000) Cytosolic phospholipase A2 is required for the activation of the NADPH oxidase associated H+ channel in phagocyte-like cells. Adv Exp Med Biol 479:125–135. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ et al (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142(5):687–698. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Raptis DA, Limani P, Jang JH, Ungethum U, Tschuor C, Graf R, Humar B, Clavien PA (2014) GPR120 on Kupffer cells mediates hepatoprotective effects of omega3-fatty acids. J Hepatol 60(3):625–632. CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Wellhauser L, Belsham DD (2014) Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons. J Neuroinflammation 11:60. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Amos D, Cook C, Santanam N (2019) Omega 3 rich diet modulates energy metabolism via GPR120-Nrf2 crosstalk in a novel antioxidant mouse model. Biochim Biophys Acta Mol Cell Biol Lipids 1864(4):466–488. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Ren Z, Chen L, Wang Y, Wei X, Zeng S, Zheng Y, Gao C, Liu H (2019) Activation of the omega-3 fatty acid receptor GPR120 protects against focal cerebral ischemic injury by preventing inflammation and apoptosis in mice. J Immunol 202(3):747–759. CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Korbecki J, Bobinski R, Dutka M (2019) Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflamm Res 68(6):443–458. CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A 94(9):4312–4317. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Krey G, Braissant O, L’Horset F, Kalkhoven E, Perroud M, Parker MG, Wahli W (1997) Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 11(6):779–791. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM et al (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3(3):397–403CrossRefGoogle Scholar
  89. 89.
    Wang L, Chen K, Liu K, Zhou Y, Zhang T, Wang B, Mi M (2015) DHA inhibited AGEs-induced retinal microglia activation via suppression of the PPARgamma/NFkappaB pathway and reduction of signal transducers in the AGEs/RAGE axis recruitment into lipid rafts. Neurochem Res 40(4):713–722. CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Cho HY, Gladwell W, Wang X, Chorley B, Bell D, Reddy SP, Kleeberger SR (2010) Nrf2-regulated PPAR{gamma} expression is critical to protection against acute lung injury in mice. Am J Respir Crit Care Med 182(2):170–182. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Ikeda Y, Sugawara A, Taniyama Y, Uruno A, Igarashi K, Arima S, Ito S, Takeuchi K (2000) Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator-activated receptor gamma in macrophages via an interaction with NRF2. J Biol Chem 275(42):33142–33150. CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Polvani S, Tarocchi M, Galli A (2012) PPARgamma and oxidative stress: con(beta) catenating NRF2 and FOXO. PPAR Res 2012:641087. CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Shih AY, Imbeault S, Barakauskas V, Erb H, Jiang L, Li P, Murphy TH (2005) Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J Biol Chem 280(24):22925–22936. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Wardyn JD, Ponsford AH, Sanderson CM (2015) Dissecting molecular cross-talk between Nrf2 and NF-kappaB response pathways. Biochem Soc Trans 43(4):621–626. CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Zhao XR, Gonzales N, Aronowski J (2015) Pleiotropic role of PPARgamma in intracerebral hemorrhage: an intricate system involving Nrf2, RXR, and NF-kappaB. CNS Neurosci Ther 21(4):357–366. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Bradley MA, Xiong-Fister S, Markesbery WR, Lovell MA (2012) Elevated 4-hydroxyhexenal in Alzheimer’s disease (AD) progression. Neurobiol Aging 33(6):1034–1044. CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Lovell MA, Bradley MA, Fister SX (2012) 4-Hydroxyhexenal (HHE) impairs glutamate transport in astrocyte cultures. J Alzheimer’s Disease: JAD 32(1):139–146. CrossRefGoogle Scholar
  98. 98.
    Figueroa JD, Cordero K, Baldeosingh K, Torrado AI, Walker RL, Miranda JD, Leon MD (2012) Docosahexaenoic acid pretreatment confers protection and functional improvements after acute spinal cord injury in adult rats. J Neurotrauma 29(3):551–566. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Yang YC, Lii CK, Wei YL, Li CC, Lu CY, Liu KL, Chen HW (2013) Docosahexaenoic acid inhibition of inflammation is partially via cross-talk between Nrf2/heme oxygenase 1 and IKK/NF-kappaB pathways. J Nutr Biochem 24(1):204–212. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Huang Y, Li W, Kong AN (2012) Anti-oxidative stress regulator NF-E2-related factor 2 mediates the adaptive induction of antioxidant and detoxifying enzymes by lipid peroxidation metabolite 4-hydroxynonenal. Cell Biosci 2(1):40. CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Chen ZH, Saito Y, Yoshida Y, Sekine A, Noguchi N, Niki E (2005) 4-Hydroxynonenal induces adaptive response and enhances PC12 cell tolerance primarily through induction of thioredoxin reductase 1 via activation of Nrf2. J Biol Chem 280(51):41921–41927. CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Maulucci G, Daniel B, Cohen O, Avrahami Y, Sasson S (2016) Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells. Mol Asp Med 49:49–77. CrossRefGoogle Scholar
  103. 103.
    Jazwa A, Cuadrado A (2010) Targeting heme oxygenase-1 for neuroprotection and neuroinflammation in neurodegenerative diseases. Curr Drug Targets 11(12):1517–1531CrossRefGoogle Scholar
  104. 104.
    Pizzimenti S, Ciamporcero E, Daga M, Pettazzoni P, Arcaro A, Cetrangolo G, Minelli R, Dianzani C et al (2013) Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front Physiol 4:242. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Barone E, Di Domenico F, Cassano T, Arena A, Tramutola A, Lavecchia MA, Coccia R, Butterfield DA et al (2016) Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: a new paradigm. Free Radic Biol Med 91:127–142. CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Barone E, Di Domenico F, Cenini G, Sultana R, Cini C, Preziosi P, Perluigi M, Mancuso C et al (2011) Biliverdin reductase—a protein levels and activity in the brains of subjects with Alzheimer disease and mild cognitive impairment. Biochim Biophys Acta 1812(4):480–487. CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Barone E, Di Domenico F, Cenini G, Sultana R, Coccia R, Preziosi P, Perluigi M, Mancuso C et al (2011) Oxidative and nitrosative modifications of biliverdin reductase-A in the brain of subjects with Alzheimer’s disease and amnestic mild cognitive impairment. J Alzheimer’s Disease: JAD 25(4):623–633. CrossRefGoogle Scholar
  108. 108.
    Barone E, Di Domenico F, Sultana R, Coccia R, Mancuso C, Perluigi M, Butterfield DA (2012) Heme oxygenase-1 posttranslational modifications in the brain of subjects with Alzheimer disease and mild cognitive impairment. Free Radic Biol Med 52(11–12):2292–2301. CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Sharma N, Tramutola A, Lanzillotta C, Arena A, Blarzino C, Cassano T, Butterfield DA, Di Domenico F et al (2019) Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer’s disease. Neurobiol Dis 125:176–189. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Di Domenico F, Tramutola A, Butterfield DA (2017) Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of Alzheimer disease and other selected age-related neurodegenerative disorders. Free Radic Biol Med 111:253–261. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Shringarpure R, Grune T, Sitte N, Davies KJ (2000) 4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer’s disease. Cell Mol Life Sci 57(12):1802–1809CrossRefGoogle Scholar
  112. 112.
    Montine KS, Kim PJ, Olson SJ, Markesbery WR, Montine TJ (1997) 4-hydroxy-2-nonenal pyrrole adducts in human neurodegenerative disease. J Neuropathol Exp Neurol 56(8):866–871. CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A et al (2005) Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem 92(3):628–636. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Richard and Loan Hill Department of BioengineeringUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of ChemistryUniversity of MissouriColumbiaUSA
  3. 3.Department of BiochemistryUniversity of MissouriColumbiaUSA
  4. 4.Department of Anatomy and Cell BiologyUniversity of Illinois at ChicagoChicagoUSA
  5. 5.UIC Bioengineering (MC 063)ChicagoUSA

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